Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells

Hefti, Martin; Albert, Ina; Luginbühl, Vera

doi:10.1007/s11060-012-0857-9

Publication type:	Article in scientific journal
Type of review:	Peer review (publication)
Title:	Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells
Authors:	Hefti, Martin Albert, Ina Luginbühl, Vera
DOI:	10.1007/s11060-012-0857-9
Published in:	Journal of Neuro-Oncology
Volume(Issue):	108
Issue:	3
Page(s):	443
Pages to:	450
Issue Date:	2012
Publisher / Ed. Institution:	Springer
ISSN:	0167-594X 1573-7373
Language:	German
Subjects:	Fluorescence-guided surgery; Photodynamic therapy; Glioblastoma multiforme; 5-Aminolevulinic acid; Brain Tumor
Subject (DDC):	615: Pharmacology and therapeutics 616: Internal medicine and diseases
Abstract:	Epileptic seizures are among the presenting clinical signs of malignant glioma patients, frequently necessitating treatment with antiepileptic drugs (AEDs). The efficacy of 5-aminolevulinic acid (5-ALA)-based intraoperative fluorescence-guided surgery and photodynamic therapy (PDT) in glioblastoma multiforme (GBM) patients depends on the specific accumulation and total amount of intracellularly synthesized protoporphyrin IX (PpIX) in tumour cells. In this study, we investigated the effect of the AEDs phenytoin (PHY) and levetiracetam (LEVE) on 5-ALA-induced PpIX accumulation in two glioma cell lines (U373 MG and U-87 MG) and primary GBM cells isolated from a human biopsy. After treatment with PHY and LEVE for three days cells were incubated with 1 mM 5-ALA for 4 h and PpIX accumulation was determined by fluorescence measurement. We observed a decrease in PpIX synthesis of up to 55 ± 12% in primary GBM cells after incubation with phenytoin. This reduction was dose-dependent for all tested cell lines and primary GBM cells. LEVE on the other hand did not alter PpIX concentration in GBM cells. PDT was performed in vitro by irradiating the GBM cells with light doses from 0.5 to 10 J cm-2 at 627 nm after AED and 5-ALA treatment. Although less PpIX accumulated in PHY-treated cells, efficacy of PDT was not affected. We assume that damage to the mitochondrial membrane by PHY inhibits PpIX synthesis in vitro, because we showed mitochondrial dysfunction as a result of reduced mitochondrial membrane potential in PHY-treated cells. No change in glutathione status was observed. To evaluate further the effect of PHY on PpIX fluorescence, and to establish its significance in clinical practice, animal and clinical studies are required, because the results presented here imply PHY may reduce intracellular accumulation of PpIX in patients with highgrade gliomas.
URI:	https://digitalcollection.zhaw.ch/handle/11475/12923
Fulltext version:	Published version
License (according to publishing contract):	Licence according to publishing contract
Departement:	Life Sciences and Facility Management
Organisational Unit:	Institute of Chemistry and Biotechnology (ICBT)
Appears in collections:	Publikationen Life Sciences und Facility Management

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Hefti, M., Albert, I., & Luginbühl, V. (2012). Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells. Journal of Neuro-Oncology, 108(3), 443–450. https://doi.org/10.1007/s11060-012-0857-9

Hefti, M., Albert, I. and Luginbühl, V. (2012) ‘Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells’, Journal of Neuro-Oncology, 108(3), pp. 443–450. Available at: https://doi.org/10.1007/s11060-012-0857-9.

M. Hefti, I. Albert, and V. Luginbühl, “Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells,” Journal of Neuro-Oncology, vol. 108, no. 3, pp. 443–450, 2012, doi: 10.1007/s11060-012-0857-9.

HEFTI, Martin, Ina ALBERT und Vera LUGINBÜHL, 2012. Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells. Journal of Neuro-Oncology. 2012. Bd. 108, Nr. 3, S. 443–450. DOI 10.1007/s11060-012-0857-9

Hefti, Martin, Ina Albert, and Vera Luginbühl. 2012. “Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells.” Journal of Neuro-Oncology 108 (3): 443–50. https://doi.org/10.1007/s11060-012-0857-9.

Hefti, Martin, et al. “Phenytoin reduces 5-aminolevulinic acid-induced protoporphyrin IX accumulation in malignant glioma cells.” Journal of Neuro-Oncology, vol. 108, no. 3, 2012, pp. 443–50, https://doi.org/10.1007/s11060-012-0857-9.